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Review
. 2020 Jan 2;40(1):12-21.
doi: 10.1523/JNEUROSCI.0733-19.2019.

Revisiting the Stress Concept: Implications for Affective Disorders

Bruce S McEwen  1 , Huda Akil  2
Affiliations
Review

Revisiting the Stress Concept: Implications for Affective Disorders

Bruce S McEwen et al. J Neurosci. .

Abstract

Over the last 50 years, the concept of stress has evolved significantly, and our understanding of the underlying neurobiology has expanded dramatically. Rather than consider stress biology to be relevant only under unusual and threatening conditions, we conceive of it as an ongoing, adaptive process of assessing the environment, coping with it, and enabling the individual to anticipate and deal with future challenges. Though much remains to be discovered, the fundamental neurocircuitry that underlies these processes has been broadly delineated, key molecular players have been identified, and the impact of this system on neuroplasticity has been well established. More recently, we have come to appreciate the critical interaction between the brain and the rest of the body as it pertains to stress responsiveness. Importantly, this system can become overloaded due to ongoing environmental demands on the individual, be they physical, physiological, or psychosocial. The impact of this overload is deleterious to brain health, and it results in vulnerability to a range of brain disorders, including major depression and cognitive deficits. Thus, stress biology is one of the best understood systems in affective neuroscience and is an ideal target for addressing the pathophysiology of many brain-related diseases. The story we present began with the discovery of glucocorticoid receptors in hippocampus and has extended to other brain regions in both animal models and the human brain with the further discovery of structural and functional adaptive plasticity in response to stressful and other experiences.

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Figures

Figure 1.
Figure 1.
The brain is a primary organ that perceives and responds to what is stressful to an individual. The major function of cortisol and other mediators of allostasis is to promote adaptation. However, overuse and/or dysregulation among the mediators of allostasis lead to allostatic load (or overload) and accelerate disease processes such as cardiovascular disease, diabetes, and affective disorders. Three limbic brain regions are noted.
Figure 2.
Figure 2.
Key elements of the limbic HPA. Glucocorticoids feed back to the brain to restrain the stress response. They produce their actions via GRs and MRs, which are generally classified as ligand-dependent transcription factors that are expressed in multiple brain regions, especially the hippocampus. Glucocorticoid effects in the brain involve not only direct and indirect genomic actions, but also direct stimulation of glutamate release and stimulation of endocannabinoid production, which then feed back on glutamate and GABA release and actions in mitochondria to affect Ca2+ buffering and free radical formation. BDNF, in the presence of glucocorticoids, phosphorylates the GR at sites that facilitate its translocation to the cell nucleus for transcriptional actions; this effect is synergistic with the ability of glucocorticoids to promote the phosphorylation of the TrkB receptor independently of BDNF. Table 1 refers to mechanistic studies of mediators and cellular processes that are involved in the remodeling of neurons in hippocampus, amygdala, and prefrontal cortex.
Figure 3.
Figure 3.
Glucocorticoids, excitatory amino acids and other mediators and processes noted in Table 1 operate in a nonlinear, biphasic manner to promote adaptive plasticity, on the one hand, and to impair resilience and promote damage, on the other hand. Lack of resilience in the aftermath of stressful experiences needs external intervention, as is the case for affective disorders.
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References

    1. Akana SF, Jacobson L, Cascio CS, Shinsako J, Dallman MF (1988) Constant corticosterone replacement normalizes basal adrenocorticotropin (ACTH) but permits sustained ACTH hypersecretion after stress in adrenalectomized rats. Endocrinology 122:1337–1342. 10.1210/endo-122-4-1337 - DOI - PubMed
    1. Akil H, Watson SJ, Young E, Lewis ME, Khachaturian H, Walker JM (1984) Endogenous opioids: biology and function. Annu Rev Neurosci 7:223–255. 10.1146/annurev.ne.07.030184.001255 - DOI - PubMed
    1. Akil H, Gordon J, Hen R, Javitch J, Mayberg H, McEwen B, Meaney MJ, Nestler EJ (2018) Treatment resistant depression: a multi-scale, systems biology approach. Neurosci Biobehav Rev 84:272–288. 10.1016/j.neubiorev.2017.08.019 - DOI - PMC - PubMed
    1. Arriza JL, Weinberger C, Cerelli G, Glaser TM, Handelin BL, Housman DE, Evans RM (1987) Cloning of human mineralocorticoid receptor complementary DNA: structural and functional kinship with the glucocorticoid receptor. Science 237:268–275. 10.1126/science.3037703 - DOI - PubMed
    1. Aurbach EL, Inui EG, Turner CA, Hagenauer MH, Prater KE, Li JZ, Absher D, Shah N, Blandino P Jr, Bunney WE, Myers RM, Barchas JD, Schatzberg AF, Watson SJ Jr, Akil H (2015) Fibroblast growth factor 9 is a novel modulator of negative affect. Proc Natl Acad Sci U S A 112:11953–11958. 10.1073/pnas.1510456112 - DOI - PMC - PubMed

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